The study of the well-known association of immunodeficiency diseases and cancer susceptibility has recently shifted from clinical and epidemiological correlation into the molecular and cellular biology fields. Analysis of human patients and mouse models has shown that immunodeficiency and increased risk of cancer can in some cases be the direct effects of the same underlying mutation in one of the factors involved in antigen receptor gene rearrangement and DNA repair/cell cycle control, such as the cell cycle checkpoint regulator, atm (which is mutated in ataxia telangiectasia) and the Ku70 DNA repair factor. In addition, an association between impaired immunoglobulin G (IgG) production and increased cancer susceptibility has been found in mismatch repair-deficient mice. Together with other findings, these latter observations have indicated an involvement of DNA repair pathways in immunoglobulin class switch recombination. We have identified a new type of humoral immunodeficiency in SENCAR/A mice, a widely studied model of genetic susceptibility to carcinogenesis. This novel immune phenotype includes low serum IgG3 levels, absence of IgG responses to T-independent antigens, and low IgG2b switching in vitro. We have shown that the immunodeficiency is inherited as a co-dominant, monogenic trait, and that it is absent in a SENCAR-related strain that has also lost one of the cancer susceptibility loci. This phenotype is unique, although it resembles, in some aspects, that of DNA mismatch repair mutant mice and some human immunodeficiency syndromes. We propose to test the hypothesis that the novel immunodeficiency and the cancer susceptibility phenotypes of SENCAR/A mice are genetically and functionally linked, possibly due to a defect in DNA repair. We will characterize the SENCAR/A defect at the molecular level by establishing its impact on the mechanism of class switch recombination, and we will apply a genetic assay to unveil underlying DNA repair deficiencies. Moreover, we will use linkage analysis and positional cloning techniques to map and identify the affected gene, and to establish its potential involvement in cancer susceptibility.